Process for preparing 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds

ABSTRACT

6-(Substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds possessing strong platelet aggregation inhibiting activity and blood pressure depressing activity, having the general formula: ##STR1## wherein R 1  is hydrogen or lower alkyl; R 2  is hydrogen, lower alkyl, lower alkylthio or the grouping R 5  --NH-- where R 5  is lower alkyl; R 3  is phenyl, pyridyl, benzyl, lower alkyl or a substituted phenyl group carrying at any desired position on the benzene ring thereof the grouping: ##STR2## where R 1  has the same meaning as given above; R 4  is hydrogen or halogen; n is 0 or 1; and when both R 2  and R 3  are lower alkyl groups, R 2  and R 3  may be combined together with the bridging member ##STR3## between them to form the structure: ##STR4## where m is 2 or 3, as well as physiologically acceptable acid-addition salts thereof, and processes for preparing them.

This application is a divisional of copending application Ser. No.454,021, filed on Dec. 28, 1982.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to new pyridazinone derivatives possessinguseful pharmacological activities and to processes for preparing thesame. More particularly, the present invention relates to new6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds havingstrong platelet aggregation inhibiting activity and blood pressuredepressing activity and to processes for the preparation of such newpyridazinone compounds.

2. Description of the Prior Art

Certain kinds of dihydropyridazinone derivatives are known to possessuseful pharmacological activities. For example, the6-(p-acylaminophenyl)-4,5-dihydropyridazinone-(3) compounds disclosed inJapanese Laid-Open patent Application No. 54-9289 are reported topossess platelet aggregation inhibiting activity as well as bloodpressure depressing activity. A number of studies are still beingconducted to investigate useful pharmacological activities of variouspyridazinone derivatives. Under such circumstances, there is a greatdemand in this art for developing additional new classes of pyridazinonederivatives having valuable pharmacological activities.

BRIEF SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide new6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds.

It is another object of the present invention to provide newdihydropyridazinone derivatives possessing strong platelet aggregationinhibiting activity as well as blood pressure depressing activity.

It is still another object of the present invention to provide processesfor the preparation of such new dihydropyridazinone compounds.

Other objects, features an advantages of the present invention willbecome apparent more fully from the following description.

DETAILED DESCRIPTION OF THE INVENTION

With a view toward preparing a new class of pyridazinone compoundshaving valuable pharmacological activities, the present inventors haveconducted extensive research for chemically modifying6-phenyl-4,5-dihydro-3(2H)-pyridazinone by introducing various kinds ofsubstituents into the pyridazinone ring itself and/or the 6-phenyl groupthereof. As a result of such research, it has now been found that new6-phenyl-4,5-dihydro-3(2H)-pyridazinone compounds which have a specificsubstituted amidino group ##STR5## directly or indirectly bound to the4-position of the phenyl group and which may further be substituted atthe 3-position of the phenyl group and/or the 5-position of thepyridazinone group possess excellent platelet aggregation inhibitingactivity and blood pressure depressing activity and are thus valuable asblood pressure depressants, antithrombolic agents and the likemedicaments for the circulation system. The present invention is basedon this finding.

Therefore, in accordance with the present invention, there are providednew 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds ofthe general formula: ##STR6## wherein R¹ is a hydrogen atom or a loweralkyl group; R² is a hydrogen atom, a lower alkyl group, a loweralkylthio group or the grouping R⁵ --NH-- where R⁵ is a lower alkylgroup; R³ is a phenyl group, a pyridyl group, a benzyl group, a loweralkyl group or a substituted phenyl group carrying at any desiredposition on the benzene ring thereof the grouping: ##STR7## wherein R¹has the same meaning as given above; R⁴ is a hydrogen atom or a halogenatom; n is the integer 0 or 1; and when both R² and R³ are lower alkylgroups, R² and R³ may be combined together with the bridging member##STR8## between them to form the structure: ##STR9## where m is theinteger 2 or 3, as well as physiologically acceptable acid-additionsalts thereof.

The compounds of the present invention involve the following threeclasses of pyridazinone compounds:

(1) 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds ofthe general formula: ##STR10## (2) 6-[4-(1,3-diazacycloalken-2-ylaminoor -amino-alkyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone compounds of thegeneral formula: ##STR11## (3)N,N'-bis[4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl or-phenylalkyl]-acylamidine compounds of the general formula: ##STR12##

In these formulas, R² ' is a hydrogen atom, a lower alkyl group, a loweralkylthio group or the grouping R⁵ -NH--, R³ ' is a phenyl group, apyridyl group, a benzyl group or a lower alkyl group, and R¹, R⁴, R⁵, nand m have the same meanings as given above. Of the compoundsrepresented by the general formula (Ic), preferred are those in whichboth 4,5-dihydro-3(2H)-pyridazinone rings exist in symmetricalpositions.

In the compounds of the general formula (I), there is tautomerism in theamidine or guanidine structure and the following two tautomers exist incase of the amidine structure: ##STR13## and the following threetautomers exist in case of the guanidine structure: ##STR14##

The compounds of the general formula (I) can exist as such tautomers.Accordingly, these tautomers are also involved in the end products ofthe present invention.

When R¹, R², R³ and/or R⁵ in the general formula (I) represents a loweralkyl group, this group preferably has 1 to 4 carbon atoms and may belinear or branched. Typical examples of the lower alkyl group includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl andtert-butyl. Thus, examples of the lower alkylamino group of the formulaR⁵ --NH-- include methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino, isobutylamino, sec-butyl-amino andtert-butylamino. Similarly, examples of R² in case of a lower alkylthiogroup include methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio and isobutylthio. When R³ is a phenyl, pyridyl or benzylgroup, this group may further be substituted on the benzene or pyridinering by one or more lower alkyl groups having 1 to 4 carbon atoms. WhenR³ is a pyridyl group, this group may be 2-pyridyl, 3-pyridyl or4-pyridyl. Illustrative of R⁴ in case of a halogen atom are fluorine,chlorine, bromine and iodine atoms.

Since the compounds of the general formula (I) carry amino nitrogenatoms in their molecules, these compounds can form acid-addition saltswith various inorganic and organic acids. Mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid andorganic acids such as oxalic acid, succinic acid, tartaric acid andcitric acid are preferable as they form physiologically acceptableacid-addition salts with the compounds of this invention. Suchacid-addition salts can easily be converted into the free compounds bytreating the salts with an alkaline substance such as sodium hydroxide,sodium carbonate, sodium bicarbonate or sodium acetate, potassiumhydroxide, potassium carbonate or potassium bicarbonate, ammonia or astrong organic base such as methylamine or tetramethyl ammoniumhydroxide, preferably in a solvent such as water or an aqueous alcohol.

Illustrative of the typical 6-(substitutedphenyl)-4,5-dihydro-3(2H)-pyridazinone compounds of this invention are,for example,

6-[4-(N-benzyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N-butyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N-propyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N-ethyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N,N'-dimethylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N-phenyl-N'-ethylguanidino)phenyl]-5-ethyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(4-pyridyl-(2)-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[3-bromo-4-(1,3-diazacyclopenten-2-ylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(1,3-diazacyclopenten-2-ylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(1,3-diazacyclopenten-2-ylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone

6-[4-(1,3-diazacyclopenten-2-ylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(1,3-diazacyclohexen-2-ylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N,N'-dimethylguanidinomethyl)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-(N-butyl-N'-methylguanidinomethyl)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[3-bromo-4-(N-propyl-N'-ethylguanidinomethyl)-phenyl]-5-ethyl-4,5-dihydro-3(2H)-pyridazinone,

N,N'-bis[4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)phenyl]-formamidine

N,N'-bis[2-bromo-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)phenyl]-formamidine,

N,N'-bis[4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-formamidine,

N,N'-bis[4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)benzyl]-formamidine

6-[4-{N-(2-pyridyl)-formamidino}phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-{N-(3-pyridyl)-formamidino}phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,

6-[4-{N-(4-pyridyl)-formamidino}phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,and

N,N'-bis[4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)phenyl]-acetamidine,as well as physiologically acceptable acid-addition salts thereof withvarious mineral acids and organic acids.

In accordance with the present invention, there is also provided aprocess for the preparation of the new 6-(substitutedphenyl)-4,5-dihydro-3(2H)-pyridazinone compounds of the general formula(I) through several different routes.

In one embodiment of the preparation process, the compounds of thegeneral formula (I) can be prepared by first reacting 6-(3-R⁴ -4-amino-or 3-R⁴ -4-amino-alkyl-phenyl)-4,5-dihydro-3(2H)-pyridazinone with athioisocyanate of the formula: R³ -NCS in a usual manner to form athiourea derivative of the general formula: ##STR15## wherein R¹, R³ ',R⁴ and n have the same meanings as given above, reacting this thioureaderivative with a methyl halide (usually, methyl iodide) to prepare thecorresponding methylisothiuronium salt (usually, the hydroiodide) of thegeneral formula: ##STR16## wherein X is a halogen atom and R¹, R³ ', R⁴and n have the same meanings as given above, according to a method knownper se, and then reacting the methylisothiuronium salt of the formula(II') in a proper solvent with a suitable amine.

Illustrative of the solvent suitably used for the reaction are, forexample, water, methanol, ethanol, propanol and dimethylformamide(referred to hereinafter simply as DMF). Examples of the amine used forthis reaction include alkyl-amines such as methylamine, ethylamine,propylamine, isopropylamine and butylamine, aniline, benzylamine, 2-, 3-and 4-aminopyridines, ethylenediamine and trimethylenediamine.

In another embodiment of the process of this invention, the compounds ofthe general formula (I) wherein R² is a hydrogen atom or a lower alkylgroup can be prepared by utilizing a general method known as a syntheticmethod for amidines. For example, such compounds can be prepared byreacting an imidate or an imidoyl halide of the general formula:##STR17## wherein R² ' is a hydrogen atom or a lower alkyl group, R³ "is a phenyl or pyridyl group, and X is a halogen atom, especially achlorine atom, or a lower alkoxy group such as methoxy or ethoxy, in anappropriate solvent with a pyridazinone derivative of the generalformula: ##STR18## wherein R¹, R⁴ and n have the same meanings as givenabove.

Illustrative of the solvent suitably used for this reaction are, forexample, benzene, toluene, ethanol and DMF.

In still another embodiment of the process of this invention, some ofthe compounds of the general formula (I) can be prepared by heating acompound of the general formula (IV) with a lower alkyl orthoformate ororthoacetate such as ethyl orthoformate or ethyl orthoacetate in thepresence of p-toluenesulfonic acid or the like, if necessary, in asolvent such as toluene or DMF, to effect condensation while removinglower alkanols formed during the condensation reaction.

The compounds of the general formula (I) thus obtained are new chemicalsubstances and exhibit strong platelet aggregation inhibiting activityand blood pressure depressing activity. Accordingly, the compounds ofthe present invention are useful as valuable medicaments for the remedyand prevention of thrombotic diseases and hypertension. Pharmaceuticalformulation of the compounds of the general formula (I) and theirphysiologically acceptable salts can be effected by means of anon-chemical route. In order to accomplish this, the compounds andphysiologically acceptable acid addition salts are brought into asuitable dosage form, together with at least one solid, liquid and/orsemi-solid excipient or auxiliary, if necessary, with one or more otheractive ingredients.

The pharmakinetic effects of the new compounds of this invention areexamined according to the following testing methods;

(1) Platelet aggregation inhibiting activity:

The influence on the aggregation of platelets was examined according tothe Born method [G. V. Born, Nature 194, 927 (1962)]. Blood extracted byinserting a cannula into the carotid artery of a rabbit undernon-anesthetic conditions was mixed with a 3.8% solution of sodiumcitrate in a mixing ratio of 9:1 and the mixture was subjected tocentrifugal action for 10 minutes at 1100 r.p.m., using a laboratorycentrifugal separator, whereby red blood corpuscles were precipitated toyield a plasma rich in platelets (referred to hereinafter simply asPRP). A small amount of PRP was placed in a cubette of an Aglygometerand stirred with a small stirrer. To the PRP were added successively asolution of a substance to be tested (pH 7.4, physiologically isotonic)and collagen to initiate the aggregation of platelets. The difference intransmission of PRP in the process of aggregation was continuouslyrecorded. The amount of collagen added for initiating the aggregationwas set to a minimum amount, thus enabling observation of the maximumaggregation. The strength of inhibiting the aggregation by the substanceto be tested was calculated from the concentration of the substance tobe tested which exhibited the same inhibiting effect as shown by 10⁻⁴ Maspirin. A result of this experiment is shown in Table 1 wherein therating of the aggregation-inhibiting effect is designated by thefollowing symbols:

---No inhibiting effect

±--Weaker in the aggregation-inhibiting effect than aspirin

+--Equivalent in the aggregation-inhibiting effect to aspirin

++--Below 10 times as much in the aggregation-inhibiting effect asaspirin

+++--Below 100 times as much in the aggregation-inhibiting effect asaspirin

++++--Above 100 times as much in the aggregation-inhibiting effect asaspirin

(2) Anti-hypertensive activity:

After the development of hypertension in rats that were at least 20weeks old, spontaneously hypertensive rats (SHR) were starved for 17hours and used for the test. The sistolic blood pressure of the tailartery was measured by an indirect method under non-anestheticconditions before administration of a medicament and 1, 2, 4, 6 and 24hours after administration of the medicament. The substance to be testedwas dissolved or suspended in a 0.2% CMC solution and orallyadministered to a group consisting of 3-5 rats showing a sistolic bloodpressure of 180 mm Hg or higher. A result of the experiments is shown inTable 1.

                  TABLE 1                                                         ______________________________________                                                                            Platelets                                                  sistolic blood pressure                                                                          aggrega-                                  Compounds        (mm Hg)            tion in-                                  of Exam-                                                                              Dosage   Hours elapsed      hibiting                                  ple Nos.                                                                              (mg/kg)  0      2    4    6    24   activity                          ______________________________________                                        1 - (c) 4        190    190  183  --   --   +++                               2       4        190    140  140  152  177  +++                               7       4        183    183  183  --   --   ++                                8       4        187    144  139  139  160  ±                              9       4        193    145  148  146  181  +++                               ______________________________________                                    

The following examples are given merely as illustrative of the presentinvention and are not to be considered as limiting.

EXAMPLE 1

(a)6-[4-(N-methylthiocarbamoylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone

In 40 ml of dry dimethylformamide (DMF) was dissolved 8.13 g of6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone. To thissolution was added 3.5 g of methyl thioisocyanate, and the mixture wasstirred for 4 hours at room temperature. The mixture was stirred for anadditional 30 minutes at 50° C. and the solvent was distilled off underreduced pressure. To the residue was added 50 ml ofdichloromethane/ether (1:1) to precipitate crystals which were thencollected by filtration and washed with dichloromethane, whereby 10.1 gof the above-identified compound was obtained. M.P. 213° C.

(b) Methylisothiuronium hydroiodide

In 100 ml of anhydrous methanol was dissolved 8.23 g of the productobtained in the preceding step (a). To this solution was added 5.11 g ofmethyl iodide, and the mixture was stirred for 2 hours at 40°-50° C. Themixture was stirred for an additional one hour under reflux. Aftercooling, the solvent was removed from the mixture by distillation toconcentrate the mixture to 20 ml. After cooling, the precipitatedcrystals were collected by filtration and washed with ether whereby 12.3g of methylisothiuronium hydroiodide was obtained. M.P. 232°-234° C.(with decomp.).

(c)6-[4-(1,3-diazacyclopenten-2-ylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone

A mixture of 2.09 g of the compound obtained in the foregoing step (b),450 mg of ethylenediamine and 15 ml of ethanol was stirred for 16 hoursunder reflux. The solvent was distilled off and the residue was taken upin a small amount of methanol. 10 Milliliters of a 30% aqueous solutionof potassium hydroxide was added to the methanolic solution and theprecipitated crystals were collected by filtration, washed with waterand then with a small amount of methanol, whereby 1.1 g of theabove-identified compound was obtained. M.P. 270°-272° C. (withdecomp.).

EXAMPLE 2

6-[4-(N-butyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinonehydrochloride

Using the compound obtained in Example 1(b) and butylamine, the reactionwas carried out in the same manner as described in Example 1(c) toobtain the above-identified compound.

EXAMPLE 3

6-[4-(N-propyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinonehydrochloride

Using the compound obtained in Example 1(b) and propylamine, thereaction was carried out in the same manner as described above to obtainthe above-identified compound.

EXAMPLE 4

6-[4-(N-benzyl-N'-methylguanidino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinonehydrochloride

Using the compound obtained in Example 1(b) and benzylamine, thereaction was carried out in the same manner as described in Example 2 toobtain the above-identified compound which was in the form of anamorphous powder.

EXAMPLE 56-[3-bromo-4-(1,3-diazacyclopenten-2-ylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone

Using 6-(4-amino-3-bromophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinoneand methylthioisocyanate, the reaction was carried out in the samemanner as described in Example 1(b) to the correspondingmethylisothiuronium salt which was then reacted with ethylenediamine inthe same manner as described in Example 1(c) to afford theabove-identified compound. M.P. 265°-267° C. (with decomp.).

EXAMPLE 6

6-[4-(N,N'-dimethylguanidinomethyl)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone

(a) Reaction of6-[4-(3-methylthioureidomethyl)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinonewith methyl iodide was carried out in the same manner as described inExample 1(b) to obtain the corresponding methylisothiuroniumhydroiodide.

(b) In 2 ml of methanol was dissolved the methylisothiuroniumhydroiodide obtained in the preceding step (a). To this solution wasadded 4 ml of a 40% aqueous solution of methylamine, and the mixture wasstirred for 6 hours at room temperature. After removing the solvent fromthe mixture by distillation, 2-N hydrochloric acid was added to theresidue and any insoluble matter was eliminated. To this acidic solutionwas added 10-N potassium hydroxide in order to make the solutionstrongly alkaline. The solution was then extracted with dichloromethaneand the organic phase was dried. The solvent was distilled off and etherwas added to the residue to effect crystallization, whereby 1.1 g of thecompound identified in the heading,6-[4-(N,N'-dimethylguanidinomethyl)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone,was obtained. M.P. 190°-192° C. (with decomp.).

EXAMPLE 7

6-[4-(1,3-diazacyclopenten-2-ylaminomethyl)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone

Using the methylisothiuronium salt obtained in Example 6(a) andethylenediamine, the reaction was carried out in the same manner asdescribed in Example 1(c) to obtain the above-identified compound in theform of an amorphous powder.

EXAMPLE 8

N,N'-bis[4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-formamidin

In 20 ml of DMF was dissolved 2.03 g of6-(p-amino-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone. To thissolution were added 10 ml of ethyl orthoformate and a small amount ofp-toluenesulfonic acid, and the mixture was heated under agitation for 2hours in a steam bath. After cooling, the precipitated crystals werecollected by filtration and recrystallized from water-DMF, whereby 1.2 gof the compound identified in the heading herein was obtained. M.P.306°-308° C.

EXAMPLE 9

6-[4-{N-(2-pyridyl)-formamidino}phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone

In 15 ml of DMF was dissolved 1.52 g of6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone. To thissolution was added 1.35 g of N-(2-pyridyl)formiminoethyl ether preparedfrom 2-aminopyridine and ethyl orthoformate, and the mixture was stirredfor one hour at 60° C. After cooling, the precipitated crystals werecollected by filtration and washed with dichloromethane-DMF, whereby 2.1g of the above-identified compound was obtained. M.P. 243°-245° C.

It is to be understood that the preceding representative examples may bevaried within the scope of the present specification, both as to thereactants and reaction conditions, by one skilled in the art to achieveessentially the same results.

As many apparently widely different embodiments of this invention may bemade without departing from the spirit and scope thereof, it is to beunderstood that this invention is not limited to the specificembodiments thereof except as defined in the appended claims.

What is claimed is:
 1. A process for the preparation of a 6-(substitutedphenyl)-4,5-dihydro-3(2H)-pyridazinone compound of the formula:##STR19## wherein R¹ is a hydrogen atom or a lower alkyl group; R² is ahydrogen atom, a lower alkyl group, a lower alkylthio group or thegrouping R⁵ -NH--where R⁵ is a lower alkyl group; R³ is a phenyl group,a pyridyl group, a benzyl group, a lower alkyl group or a substitutedphenyl group carrying at the para-position (4-position) on the benzenering thereof the grouping: ##STR20## wherein R¹ has the same meaning asgiven above; R⁴ is a hydrogen atom or a halogen atom; n is 0 or 1; andwhen both R² and R³ are lower alkyl groups, R² an R³ may be combinedtogether with the bridging member ##STR21## between them to form thestructure: ##STR22## wherein m is 2 or 3, or a physiologicallyacceptable acid-addition salt thereof, which comprises reacting a6-(3-R⁴ -4-amino- or 3-R⁴-4-aminoalkyl-phenyl)-4,5-dihydro-3(2H)-pyridazinone with athioisocyanate of the formula R³ '-NCS where R³ ' is a phenyl, pyridylor benzyl group or a lower alkyl group to form a thiourea derivative ofthe formula: ##STR23## wherein R¹, R³ ', R⁴ and n have the same meaningsas given above, reacting the thiourea derivative with a methyl halide toprepare the corresponding methylisothiuronium salt of the formula:##STR24## wherein X is a halogen atom and R¹, R³ ', R⁴ and n have thesame meanings as given above, and then reacting the methylisothiuroniumsalt with an amine or diamine of the formula: ##STR25## wherein R is apyridyl, benzyl or phenyl group or a lower alkyl group and m is 2 or 3.2. A process according to claim 1, further comprising the step ofconverting the compound resulting from the reaction with the amine ordiamine into a physiologically acceptable acid-addition salt.
 3. Aprocess for the preparation of a 6-(substitutedphenyl)-4,5-dihydro-3(2H)-pyridazinone compound of the formula:##STR26## wherein R¹ is a hydrogen atom or a lower alkyl group; R² ' isa hydrogen atom or a lower alkyl group; R³ ' is a phenyl or pyridylgroup; and R⁴ is a hydrogen atom or a halogen atom, or a physiologicallyacceptable acid-addition salt thereof, which comprises reacting animidate or an imidoyl halide of the formula: ##STR27## where R² ' and R³' have the same meanings as given above and X is a halogen atom, with apyridazinone derivative of the formula: ##STR28## wherein R¹, R⁴ and nhave the same meanings as given above.
 4. A process according to claim3, further comprisng the step of converting the resulting compound intoa physiologically acceptable salt thereof.
 5. A process for thepreparation of a 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinonecompound of the formula: ##STR29## wherein R¹ is a hydrogen atom or alower alkyl group, R⁴ is a hydrogen atom or a halogen atom and n is 0 or1, or a physiologically acceptable acid-addition salt thereof, whichcomprises reacting a pyridazinone derivative of the formula: ##STR30##wherein R¹, R⁴ and n have the same meanings as given above, with acompound of the formula: ##STR31## wherein R⁵ is a lower alkyl group andR¹ has the same meaning as given above.
 6. A process according to claim5, further comprising the step of converting the resulting compound intoa physiologically acceptable salt thereof.
 7. A process according toclaim 1, wherein said methyl halide is methyl iodide.
 8. A processaccording to claim 1, wherein said amine or diamine is a member selectedfrom the group consisting of methylamine, ethylamine, propylamine,isopropylamine, butylamine, aniline, benzylamine, 2-, 3- and4-aminopyridines, ethylenediamine and trimethylenediamine.
 9. A processaccording to claim 2, wherein said compound of the formula (I) isconverted into a physiologically acceptable acid-addition salt thereofby reaction with a member selected from the group consisting ofhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalicacid, succinic acid, tartaric acid and citric acid.
 10. A processaccording to claim 4, wherein said compound of the formula (I) isconverted into a physiologically acceptable acid-addition salt thereofby reaction with a member selected from the group consisting ofhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalicacid, succinic acid, tartaric acid and citric acid.
 11. A processaccording to claim 5, wherein said compound of the formula (V) isethylorthoformate or ethylorthoacetate.
 12. A process according to claim6, wherein said compound of the formula (I) is converted into aphysiologically acceptable acid-addition salt thereof by reaction with amember selected from the group consisting of hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, succinicacid, tartaric acid and citric acid.